Study design and patients
This was a phase 3, randomized, double-blind, multicenter, active-controlled, parallel-group, noninferiority study conducted at 15 sites in China from October 2019 to November 2020 (ClinicalTrials.gov registry number NCT04052620, 12 August 2019). It was designed to evaluate the efficacy and safety of DDEA 2.32% gel BID compared with DDEA 1.16% gel QID in patients with acute ankle sprain. The primary objective was to demonstrate noninferiority between DDEA 2.32% gel BID and DDEA 1.16% gel QID on day 5. Patients were randomized 1:1 to receive DDEA 2.32% gel applied BID or DDEA 1.16% gel applied QID. Patients in the BID group also received placebo BID so that all participants had 4 daily topical applications. Trial investigators enrolled patients, and a Centralized Randomization Center using an Interactive Response Technology was used to randomly allocate participants to treatment groups. Participants, care providers, investigators, and outcomes assessors were blinded.
The final study protocol and amendments, informed consent, and other relevant information were approved by ethics committees at each of the following 15 participating sites in accordance with China’s good clinical practice and other applicable China-specific requirements:
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Ruijin Hospital Ethics Committee
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Ethics Committee of Shanghai General Hospital Institutional Review Board
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Shanghai East Hospital Ethics Committee
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Ethics Committee of The No. 920 Hospital Ethics Committee of the Joint Logistic Support
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Force of the People’s Liberation Army
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Shanghai Fengxian District Central Hospital Ethics Committee
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Shanghai Pudong Hospital Ethics Committee
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Ethics Committee of Affiliated Zhongshan Hospital of Dalian University
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Beijing Pinggu Hospital Ethics Committee
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Ethics Committee of Chenzhou First People’s Hospital
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Ethics Committee of The Third Hospital of Hebei Medical University
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Ethics Committee of The First Affiliated Hospital of Xi’an Jiaotong University
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Medical Ethics Committee of Shenzhen Second People’s Hospital
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Medical Ethics Committee of The University of Hong Kong - Shenzhen Hospital
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Shenyang Orthopedic Hospital Ethics Committee
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Ethics Committee of The First Affiliated Hospital of Jinan University
The study was conducted in accordance with International Conference on Harmonisation and the ethical principles of the Declaration of Helsinki. Written, informed consent was obtained from each subject prior to any study-specific procedures.
Eligible patients were 18 to 75 years of age, had experienced an acute grade I–II sprain of the ankle within the past 24 hours, experienced pain on movement (POM) of at least 50 mm on a 100-mm visual analogue scale (VAS), and received no pain medication within 24 hours prior to randomization (RICE treatment prior to randomization was permitted). Stable daily doses of aspirin (≤162 mg/day) for at least 30 days prior to the first dose of study medication for nonanalgesic reasons were permitted and were continued for the study duration. Patients with a prior grade I–III sprain of the affected ankle within 3 months, a prior grade II–III sprain, other significant injury, or surgery of the affected ankle were excluded. Other exclusion criteria included pain or instability of the affected ankle due to a prior ankle sprain, ankle sprain attributable to a known disease affecting the ligaments, any skin lesion or wound in the area to be treated, and a plan to undergo surgery during the time of study participation. Use of concomitant systemic or topical NSAIDs, steroids (injected or oral), physiotherapy or other kind of pain therapy, tranquilizers, anxiolytics, hypnotics, sedatives, amphetamines, barbiturates, benzodiazepines, cocaine, methamphetamines, opiates, phencyclidine, tetrahydrocannabinol, and traditional herbal or homeopathic treatments were not permitted during the study. Other background maintenance medications that were not specifically excluded as described above were allowed during the study, provided the patient had been stable on the medications for at least 3 months. Adhesive and/or immobilizing casts, bandages, air splints, and RICE treatment were not allowed. Use of a crutch and certain physician-approved exercises were allowed. All patients were provided with a supply of acetaminophen (500 mg) as rescue therapy.
Endpoints and assessments
The primary efficacy endpoint was the change from baseline in POM on day 5 of treatment as assessed by the patient using a 100-mm VAS. POM assessments were also conducted on days 1, 3, and 8 (±1 day). The investigator assessed POM while performing a manipulation of the ankle as the subject lay on an even horizontal surface.
Secondary efficacy variables included tenderness measured using calibrated algometers (pressure pain meter) in an area of 1 cm2 at the center of the injured area [10]; the patient indicated with a verbal cue when the onset of pain occurred. Other secondary endpoints included measures of ankle joint function using the Karlsson Scoring Scale [11, 12] and ankle swelling using the Figure of Eight Method [13]. Patients also completed a pain diary, which included pain intensity measured on a 4-point scale (0 = no pain to 3 = severe pain) and spontaneous pain relief assessed on a 5-point scale (0 = no relief to 4 = complete relief). Pain intensity and spontaneous pain relief were assessed immediately prior to the first dose and every 2 hours (±30 minutes) on day 1 and day 5 until the patient went to bed. Adverse event (AE) data were collected throughout the study and for 28 days following the last administration of study drug.
Statistical analysis
Approximately 300 patients were planned to be randomized to ensure that at least 240 evaluable patients completed the study for the per protocol (PP) population. Sample size calculations determined that approximately 120 patients per treatment arm provided 80% power to demonstrate the noninferiority of DDEA 2.32% gel BID versus DDEA 1.16% gel QID by comparing the 2-sided 95% confidence interval (CI) of the difference in mean change from baseline of the primary endpoint of VAS POM between the 2 doses with a noninferiority margin of 13 mm. This noninferiority margin was chosen based on minimally important clinical differences reported in the literature [14]. This assumed a treatment standard deviation (SD) of 22 mm and allows for a possible small true treatment difference of 5 mm in favor of DDEA 1.16% gel QID.
To ensure high similarity between treatment arms, efficacy endpoints were analyzed using the PP population, defined as all randomized patients who had no major protocol deviations and had at least 1 post-baseline POM VAS assessment. The primary noninferiority endpoint of the change from baseline in POM for DDEA 2.32% gel BID versus DDEA 1.16% gel QID at day 5 was analyzed using an analysis of covariance (ANCOVA) model with treatment and center as factors and baseline POM as a covariate to estimate the treatment difference and 2-sided 95% CI without imputation of missing data. Secondary efficacy assessments were analyzed using an ANCOVA model including treatment arm and center as main effects, and baseline values as covariates, with treatment difference and 2-sided 95% CI presented for each assessment.
Pain intensity was analyzed based on Sum of Pain Intensity Difference (SPID) scores, defined from 0 to 24 hours or 0 to 12 hours after the first dose on day 1 and 0 to 24 hours or 0 to 12 hours after the first dose on day 5. Pain relief was analyzed based on the sum of total pain relief scores (TOTPAR), defined as from 0 to 24 hours or 0 to 12 hours after the first dose on day 1 and 0 to 24 hours or 0 to 12 hours after the first dose on day 5.
Use of rescue medication was compared between treatments using the Cochran-Mantel-Haenszel method stratified by center, with the median treatment differences (2-sided 95% CI) presented using Hodges-Lehmann estimation. AEs were analyzed using the safety population, defined as all patients who received at least 1 dose of study treatment. AEs were mapped to system-organ class and preferred term using MedDRA version 23.0.